Voltage-gated sodium channels are critical elements in the control of electrical excitability of various cell types, including muscle and neuronal cells. In muscle and neuronal cells voltage-gated sodium channels are mainly responsible for the rising phase of the action potential. Voltage-gated sodium channels are composed of a single alpha subunit and one or two beta subunits. There are 10 known alpha subunit proteins, of which nine are functional as an ion channel. The different alpha subunit proteins are herein referenced to as Nav1.x, with x being an integer between 1 and 9. This labelling is in accordance with the conventions of the International Pharmacological Association (REF). Alpha subunits are large proteins of an approximate weight of 260 kDA (˜2000 amino acids), and are functional as voltage-gated sodium channels as monomeric structures. Four beta subunits are known at present. Beta subunits are smaller proteins of an approximate weight of 33-36 kDa. Beta subunits can modulate functional expression, as well as the characteristics of channel opening and closing (gating) of alpha subunits.
Five major lines of evidence support the notion that voltage-gated sodium channels are important therapeutic targets:                a) the biophysical characteristics of voltage-gated sodium channels,        b) the tissue expression pattern of voltage-gated sodium channels,        c) evidence from preclinical research,        d) the association between several congenital diseases and channelopathies of voltage-gated sodium channels, and        e) evidence from the usage of pharmacological agents active at voltage-gated sodium channels in the clinic.        
A main biophysical characteristic of voltage-gated sodium channels is the fast opening and closing (activation and inactivation) of the channel upon an appropriate voltage stimulus. These features make voltage-gated sodium channels absolutely essential in the generation of the upstroke of the action potential in most neuronal and muscle cells, and thereby central to the functionality of such tissue. Thus, inhibitory pharmacological interference with the activity of NaV's is expected to have dampening effects on excitability of such tissue. Such agents may thus be useful in the treatment of diseases that involve hyperactivity of neuronal or muscle tissue.
As outlined above, there are nine functional alpha subunits of voltage-gated sodium channels. Each of these alpha subunits has a characteristic tissue expression pattern. Tissue-specific up- or down-regulation of the expression of several of the voltage-gated sodium channels in human diseases or preclinical disease models in animals strongly supports a central role for specific voltage-gated sodium channels in distinct diseases.
Nav1.7 is expressed in human neuromas, which are swollen and hypersensitive nerves and nerve endings that are often present in chronic pain states (Acta Neurochirurgica (2002) 144(8) 803-810). Nav1.7 is also expressed in dorsal root ganglion neurons and contributes to the small tetrodoxin (TTX) sensitive component seen in these cells. Nav1.7 may thus be a potential pain target in addition to its role in neuroendocrine excitability (EMBO Journal (1995) 14(6) 1084-1090).
The present invention relates to a novel group of compounds that exhibit Nav1.7 inhibiting activity, and are therefore expected to be useful in the prophylaxis and treatment of different acute and chronic pain conditions.
WO 97/34883, WO 99/14212, WO 99/05135 and WO 99/14213 describe compounds for use in treatment of pain. The compounds described in these prior art documents bind to serotonine receptors. The compounds of the present invention have little to none activity towards the serotonine receptor. The compounds of the present invention also are contemplated to have an improved pharmacokinetic profile compared to the compounds in the prior art, including a higher oral bioavailability, a decreased clearance and a decreased volume of distribution. Without being bound to any theory, the difference in pharmacokinetic profile is believed to be due to the fact that the right hand side of the molecule is aromatic in the compounds of the present invention while this is not the case for the known compounds.